Lung volume reduction surgery (LVRS) is an effective adjunct to medical treatment for end stage emphysema. Clinical results suggest that LVRS works by eliminating areas of severely diseased and dysfunctional lung. We previously hypothesized that effective volume reduction might be possible using a non-surgical approach to cause permanent atelectasis of specific target regions. By collapsing these regions and applying a fibrin-based sealant, we have shown that it is possible to achieve lung volume reduction without surgery in a sheep model of emphysema. While these studies confirmed our initial hypothesis, they have also demonstrated several important shortcomings. BVR achieved solely by mechanical collapse and application of fibrin sealant is frequently incomplete. Only 1/2 to 1/3 of the target regions remained collapsed at 2month follow-up. Furthermore, several target regions developed tissue necrosis. To address these limitations, we have modified our approach to BVR. A new generation of reagents has been developed which modulates local cellular responses, and promotes fibroblast in-growth and scar formation without necrosis. Preliminary studies indicate that these modifications address the limitations identified in our original study. We now hypothesize that: improved BVR can be achieved using washout solution + glue reagents which cause site-specific collapse, and modulation of fibroblast and epithelial cell biology to generate controlled, efficient scar formation. The objectives of this proposal are to: 1) characterize physiological and biological responses using these improved reagents in a sheep model of emphysema, and 2) compare results to those obtained using conventional surgical therapy. We believe that by accomplishing these objectives, we can help advance this technology into the clinical arena.